Head and neck cancer accounts for approximately 6% of diagnosed malignancies in the United States, with an estimated 35,000 incidences and over 7,000 deaths every year. Head and neck squamous cell carcinoma (HNSCC) comprises the majority of head and neck cancers, with a worldwide incidence of more than 500,000 cases. Head and neck cancer patients often present in advanced stages of disease, and despite ongoing research, survival rates remain lower than other more common malignancies. Cytokines and pro-inflammatory factors have been shown to have a critical role in the various steps of malignant transformation, including tumor growth, survival, invasion, angiogenesis, and metastasis. Mitogen-activated protein kinases (MAPK), such as p38, JNK, and ERK, relay information from extracellular signals to the effectors which control these diverse cellular processes. Negative regulation of MAPK activity is provided by MAPK phosphatases (MKPs) that dephosphorylate MAPK proteins. The founding member of this class of phosphatases is mitogen-activated protein kinase phosphatase-1 (MKP-1). Initial studies revealed significant over-expression of MKP-1 in a range of human epithelial tumors, seen only in the early phases of disease with levels of MKP-1 expression falling progressively in tumors of higher histological grade and in metastases. We hypothesize low levels of MKP-1 in the HNSCC tumor microenvironment generate high levels of tumor-promoting inflammation. We will address how MKP-1's regulation of inflammatory cytokine expression via MAPK activity may affect HNSCC development and progression in the following specific aims: 1) determine the impact of MKP-1 deficiency on tumor development and progression in a carcinogen-induced oral cancer murine model; 2) elucidate the mechanism by which MKP-1 regulates expression of the cytokines IL-1b and CXCL1; 3) determine whether MKP-1 expression is deregulated in human HNSCC tissues. Understanding the role of inflammatory mediators in head and neck cancer progression may yield novel therapeutic targets for prevention and treatment. This proposed research project provides necessary mechanistic insight into the function of innate immune regulator MKP-1 in the tumor microenvironment. PUBLIC HEALTH RELEVANCE: In the United States, head and neck cancer is diagnosed in over 30,000 patients annually. However, significant improvement in patient survival rates has not been made for several decades. The deregulation of signaling pathways driving tumor development and progression is not well understood, particularly as it pertains to tumor-stromal compartment interaction. These studies will identify underlying mechanisms by which an innate immune regulator responds to neoplastic changes to modulate the tumor microenvironment.